DESCRIPTION: By 2015, approximately half of people living with HIV in the US will be >50 yr. of age but median life expectancy of HIV infected persons continues to lag behind that of HIV uninfected by approximately 10 years. What HIV infection and aging have in common is increased pro-inflammatory state and compromised immune function with demonstrable deficits in antibody (Ab) responses to influenza vaccines. Whether HIV accelerates aging or has additive effect on adverse effects of aging is unclear, but presence of HIV infection greatly increases inflammaging, immune senescence and increased risk of end-organ disorders termed HIV-associated non-AIDS (HANA) conditions that occur at younger ages than uninfected persons. This application is based on our pilot observations in three cohorts. First, virally suppressed menopausal HIV- infected women on combination antiretroviral therapy (cART) exhibited higher inflammatory cytokine profile, gut microbial translocation (MT) and cellular immune activation of CD4 T cells, CD8 T cells and macrophages in comparison to uninfected menopausal women; importantly, the immune activation status was negatively associated with influenza Ab response. Second, in a younger cohort of HIV infected patients with poor responses to influenza vaccines we identified a potential defect in the function of a novel peripheral CD4 helper subset designated as T follicular helper cell (pTfh) that bears functional resemblance to the germinal center Tfh (GC Tfh) cells, which are prime drivers of B cell differentiation into antibody secreting cells. Third, in HIV negative aged adults, B cell intrinsic TNF-alpha and higher microRNA-155 were predictive of B cell functional defects and poor antibody response to influenza vaccine. These observations underscore the implications of the inflammation/immune activation on immune dysfunction. We hypothesize that inflammation/immune activation negatively impacts the immune response to influenza vaccines in physiologic aging and in HIV disease, and the effect is compounded in the aging HIV infected population. We will conduct the proposed studies in virologicallly suppressed HIV infected patients on cART (and control HIV uninfected populations) in age strata 18- 40, 41-60, and >60 years with peripheral blood samples collected pre-vaccination, at 7 days, at 3-4 weeks and 6 month post-vaccination. Our specific aims are: 1. To investigate the nature and mechanism of the effect of immune activation on Ab responses to seasonal flu vaccination; 2. To characterize the function of peripheral T follicular helper cells in influenza antibody responses and role of immune activation on their function; and 3. To characterize B cells, T- independent responses and role of immune activation on their function. Understanding these issues is fundamentally important in the HIV+ elderly to improve vaccines and prevent vaccine preventable infectious complications.